Pharmaceutically active 2-(4-aminobutoxy)stilbenes

ABSTRACT

2-(4-aminobutoxy)stilbenes are prepared and found useful as pharmaceutical agents, particularly as anticonvulsants and skeletal muscle relaxants.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to 2-(4-aminobutoxy)stilbenes and their acidaddition salts which are pharmacologically active as anticonvulsants andskeletal muscle relaxants.

2. Description of the Prior Art

British Patent No. 1,307,436 discloses 2-(2-aminoethoxy)stilbenes and2-(3-aminopropoxy)stilbenes, which possess analgesic activity, whilethey do not possess anticonvulsant activity which is a characteristicfeature of the compounds of this invention. On the other hand, thecompound of this invention possess little, if any, analgesic activity.

SUMMARY OF THE INVENTION

Accordingly, it is an object of this invention to provide novel2-(4-aminobutoxy)stilbenes having superior anticonvulsant activity.

This and other objects of this invention as will hereinafter becomeclear have been attained by providing compounds of the formula (I):##STR1## wherein R is (1) ##STR2## wherein R₁ and R₂ which are alike ordifferent are selected from the group consisting of hydrogen and C₁ -C₅alkyl or (2) ##STR3## wherein Z is selected from the group consisting of--CH₂ --, ##STR4## wherein R₃ is C₁ -C₅ alkyl, ##STR5## wherein R₄ ishydrogen, C₁ -C₅ alkyl or C₁ -C₅ hydroxyalkyl; m and n are each integersof 0 to 7; and m+n is an integer of 1 to 7, and the acid addition saltsthereof.

This invention also relates to a method of treating convulsions andseizures or relieving skeletal muscle spasm in warm-blooded animalswhich comprises administering to said animals an effective amount fortreatment of convulsions and seizures or relief of skeletal muscle spasmof a compound of the formula (I) or the acid addition salt thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As summarized above, this invention relates to a group of compoundsuseful as pharmaceutical agents, which compounds are represented by theformula (I): ##STR6## wherein R is (1) ##STR7## wherein R₁ and R₂ whichare alike or different are selected from the group consisting ofhydrogen and alkyl of 1-5 (preferably 1-3) carbon atoms such as methyl,ethyl, propyl, butyl or pentyl, or (2) ##STR8## wherein Z is selectedfrom the group consisting of --CH₂ --, ##STR9## wherein R₃ is alkyl of1-5 (preferably 1-3) carbon atoms such as methyl, ethyl, propyl or thelike, ##STR10## wherein R₄ is hydrogen, alkyl of 1-5 (preferably 1-3)carbon atoms such as methyl, ethyl, propyl or the like, and hydroxyalkylof 1-5 (preferably 1-3) carbon atoms such as hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl or the like; m and n areeach integers of 0 to 7, preferably 0 to 5; m+n is an integer of 1 to 7,preferably 2 to 5.

Suitable examples of R in the formula (I) include amino, methylamino,dimethylamino, propylamino, dipropylamino, aziridinyl, 1-azetidinyl,1-pyrrolidinyl, piperidino, 4-methylpiperidino, 4-hydroxypiperidino,3-hydroxypiperidino, hexahydro-1-azepinyl, 4-methyl-1-piperazinyl,4-propyl-1-piperazinyl, 4-(2-hydroxyethyl)-1-piperazinyl,1-imidazolidinyl, 1-pyrazolidinyl, 3-methyl-1-imidazolidinyl,4-methylhexahydro-1,4-diazepin-1-yl, 4-(2-hydroxyethyl)hexahydro-1,4-diazepin-1-yl and the like.

Illustrative of the compounds of this invention are the following:

2-(4-aminobutoxy)stilbene

2-(4-methylaminobutoxy)stilbene

2-(4-dimethylaminobutoxy)stilbene

2-(4-ethylaminobutoxy)stilbene

2-(4-diethylaminobutoxy)stilbene

2-(4-propylaminobutoxy)stilbene

2-(4-dipropylaminobutoxy)stilbene

2-[4-(1-pyrrolidinyl)butoxy]stilbene

2-[4-(4-hydroxypiperidino)butoxy]stilbene

2-(4-piperidinobutoxy)stilbene

2-[4-(4-methylpiperidino)butoxy]stilbene

2-[4-(4-ethylpiperidino)butoxy]stilbene

2-[4-(hexahydro-1-azepinyl)butoxy]stilbene

2-[4-(4-hydroxypiperidino)butoxy]stilbene

2-[4-(3-hydroxypiperidino)butoxy]stilbene

2-[4-(4-propylpiperidino)butoxy]stilbene

2-[4-(4-methyl-1-piperazinyl)butoxy]stilbene

2-[4-(4-ethyl-1-piperazinyl)butoxy]stilbene

2-[4-(4-propyl-1-piperazinyl)butoxy]stilbene

2-[4-{4-(2-hydroxyethyl)-1-piperazinyl}butoxy]stilbene

2-[4-{4-(3-hydroxypropyl)-1-piperazinyl}butoxy]stilbene

2-[4-(2-methyl-1-pyrazolidinyl)butoxy]stilbene

2-[4-(4-methylhexahydro-1,4-diazepin-1-yl)butoxy]stilbene

2-[4-{4-(2-hydroxyethyl)hexahydro-1,4-diazepin-1-yl}butoxy]stilbene

The pharmaceutically acceptable acid addition salts of the abovecompounds are, of course, also included within the scope of thisinvention.

It will be understood that the term "pharmaceutically acceptable acidaddition salts" as used herein is intended to include non-toxic salts ofthe compounds of this invention with an anion. Representative of suchsalts are hydrochlorides, hydrobromides, sulfates, phosphates, nitrates,acetates, oxalates, succinates, adipates, propionates, tartrates,maleates, citrates, benzoates, toluenesulfonates, and methanesulfonates.

The compounds of this invention which are preferred due to their highlevel of anticonvulsant and muscle relaxant activity are those wherein Rin the above formula (I) is (1) ##STR11## wherein R₁ and R₂ are eachhydrogen or C₁ -C₃ alkyl or (2) ##STR12## wherein Z is selected from thegroup consisting of --CH₂ --, ##STR13## wherein R₃ is C₁ -C₃ alkyl,##STR14## wherein R₄ is C₁ -C₃ alkyl or C₁ -C₃ hydroxyalkyl; m and n areeach integers of 0 to 4; and m+n is an integer of 3 or 4.

Specific examples of the preferred compounds are those wherein R is a C₁-C₃ alkylamino or C₂ -C₆ dialkylamino group, or a piperazinyl,piperidino or pyrrolidinyl group any of which is unsubstituted orsubstituted with a C₁ -C₄ alkyl, hydroxy or C₁ -C₃ hydroxyalkyl group.

Of the compounds of this invention, it will be understood that thefollowing compounds are most preferred.

2-(4-dimethylaminobutoxy)stilbene

2-(4-methylaminobutoxy)stilbene

2-[4-(4-methyl-1-piperazinyl)butoxy]stilbene

2-[4-{4-(2-hydroxyethyl)-1-piperazinyl}butoxy]stilbene

2-(4-piperidinobutoxy)stilbene

2-[4-(3-hydroxypiperidino)butoxy]stilbene

2-[4-(1-pyrrolidinyl)butoxy]stilbene

2-[4-(4-propyl-1-piperazinyl)butoxy]stilbene

The compounds of this invention are prepared by reacting a2-(4-halogenobutoxy)stilbene of the formula (II): ##STR15## wherein X ishalogen, with an amine having the formula (III):

    R--H                                                       (III)

wherein R is as defined in the formula (I).

The 2-(4-halogenobutoxy)stilbene starting material can be prepared byreacting a 2-hydroxystilbene with a 1,4-dihalogenobutane in the presenceof a base.

The amine reacts with the equimolecular amount of the2-(4-halogenobutoxy)stilbene.

However, the use of the excess amine accelerates the reaction. Normally,the amount of the amine to be employed is in the range of 1 to 100moles, preferably 2 to 40 moles per mole of the2-(4-halogenbutoxy)stilbene. A large amount of the amine serves also asa solvent.

The reaction can be carried out without an added solvent. However, theuse of a reaction-inert solvent makes a homogeneous reaction possible.

Examples of such solvents are water, dioxane, tetrahydrofuran, dimethylsulfoxide, lower aliphatic alcohols and the mixture thereof.

The reaction temperature is not critical, but normally ranges from roomtemperature to 150° C., preferably from room temperature to 100° C.

The reaction time varies widely with the reaction temperature and thereactivity of the starting materials, but normally is within 40 hours.

The presence of bases which neutralize a hydrogen halide formed in thecourse of the reaction accelerates the reaction. Examples of such basesare inorganic bases such as potassium hydroxide, sodium hydroxide,potassium carbonate, sodium carbonate and the like; and tertiary aminessuch as pyridine, triethylamine and the like.

The amount of the base to be employed is normally in the range of 1 to 5moles per mole of the 2-(4-halogenbutoxy)stilbene.

When the base is absent, the 2-(4-aminobutoxy)stilbene reacts with ahydrogen halide formed during the reaction and are converted to the acidaddition salt thereof. In order to obtain a suitable acid addition salt,the excess amine and the solvent are distilled off, an aqueous solutionof a strong base such as sodium hydroxide and potassium hydroxide addedto convert the acid addition salt of the 2-(4-aminobutoxy)stilbene toits free form, which is extracted with a solvent such as ether,chloroform and benzene, and then a suitable acid is added to neutralizeits free form.

The 2-(4-aminobutoxy)stilbenes and the acid addition salts thereof whichare the products of the above reactions may be purified byrecrystallization employing a suitable solvent such as alcohol-ether.

The compounds of this invention which are useful as muscle relaxant andanticonvulsant agents can be administered by any means.

For example, administration can be parenterally, subcutaneously,intravenously, intramuscularly, or intraperitoneally. Alternatively orconcurrently, administration can be by the oral route. The dosageadministered will be dependent upon the age, health and weight of therecipient, the extent of convulsions, seizures or skeletal muscle spasm,kind of concurrent treatment if any, frequency of treatment, and thenature of the effect desired. Generally, a daily dosage of the activeingredient compound will be from about 0.5 to 50 mg per kg of bodyweight. Normally, from 1 to 30 mg per kg per day, in one or moreapplications per day is effective to obtain the desired result.

The compound of Formula I can be employed in dosage forms such astablets, capsules, powder packets, or liquid solutions, suspension, orelixirs, for oral administration, or sterile liquid formulations such assolutions or suspensions for parenteral use.

Besides the active ingredient of this invention, the composition willcontain a solid or liquid non-toxic pharmaceutical carrier for theactive ingredient. In one embodiment of a composition, the solid carriercan be a capsule of the ordinary gelatin type. In another embodiment,the active ingredient can be tableted with or without adjuvants, or putinto powder packets. These capsules, tablets or powders will generallyconstitute from about 5% to about 95% and preferably from 25% to 90% ofthe active ingredient. These dosage forms preferably contain from about5 to about 500 mg of active ingredients, with from about 25 to about 250mg being most preferred.

The pharmaceutical carrier can be a sterile liquid such as water andoils, including those of petroleum, animal, vegetable or syntheticorigin, such as peanut oil, soybean oil, mineral oil, sesame oil, andthe like.

In general, water saline, aqueous dextrose and related sugar solutions,and glycols such as polyethylene glycol are preferred liquid carriers,particularly for injectible solutions such as saline will ordinarilycontain from about 0.5% to 20% and preferably about 1 to 10% by weightof the active ingredient.

As mentioned above, oral administration can be in a suitable suspensionor syrup, in which the active ingredient normally will constitute fromabout 0.5 to 10% by weight.

The pharmaceutical carrier in such composition can be a watery vehiclesuch as an aromatic water, a syrup or a pharmaceutical mucilage.

The procedures employed for demonstrating anticonvulsant efficacy of thecompounds as set forth in the following examples are as follows:

Animals used were ddy strain male mice (20-22 g) and Wistar strain malerats (150-170 g).

Anticonvulsant actions were determined by the ability of the compoundsto prevent pentylenetetrazol (PTZ) convulsion and maximal electroshockseizure (MES), using 8 mice per group.

Anti-PTZ action was judged by the protection against tonic extensor (TE)induced by intraperitoneal injection of PTZ (100 mg/kg i.p.) (K.Nakamura et al., Arch. int. Pharmacodyn., 156 261 (1965)).

Anti-MES action was also judged by the protection against TE induced byelectroshock via a pair of ear electrodes (J. J. Piala et al., J.Pharmacol. exp. Therap., 127 55 (1959)).

The results were expressed as 50% effective dose (ED₅₀, mg/kg po) or aninhibition percentage at certain doses used.

LD₅₀ was calculated by the method of Litchfield-Wilcoxon (J. T.Litchfield and F. Wilcoxon, J. Pharmacol. exp. Therap., 96 99 (1949)).

Using the above procedures the compounds of this invention were comparedto well known antiepileptic agents, methotoin which is effective againstgrand-mal seizure and trimethadione which is effective against peti-malseizure.

The results are shown in Table 2.

The following examples are presented to further illustrate thepreparation of the compounds of this invention.

EXAMPLE 1

A solution of 5.0 g of 2-(4-bromobutoxy)stilbene, 50 ml of 50%dimethylamine aqueous solution and 50 ml of tetrahydrofuran is stirredat room temperature for 20 hours. At the end of this period,tetrahydrofuran and excess dimethylamine are distilled in vacuo,2N--NaOH aqueous solution is added, and the reaction product isextracted with ether. The ether solution is washed with saturated sodiumchloride solution and dried over anhydrous sodium sulfate. The additionof 20% HCl/ethanol gives a precipitate which is filtered and thencrystallized to yield 4.6 g (92%) of 2-(4-dimethylaminobutoxy)stilbenehydrochloride, m. p. 60°-68° C.

Analysis--Calcd. for C₂₀ H₂₅ NO.HCl (percent): C, 72.38; H, 7.90; N,4.38 Found (percent): C, 72.20; H, 8.23; N, 4.30

Various 2-(4-aminobutoxy)stilbenes were prepared according to theprocedure described in Example 1 using the appropriate startingmaterials.

The results are summarized in Table 1.

                                      TABLE 1                                     __________________________________________________________________________     ##STR16##               Addition                                                                                 Lower: FoundUpper: Calcd.Analysis                                            (%)                                        No.                                                                                 R                 moiety                                                                             m.p. (°C.)                                                                   C  H  N                                    __________________________________________________________________________        ##STR17##           HCl   60   72.38 72.20                                                                      7.90 8.23                                                                        4.38 4.30                            2                                                                                 ##STR18##           HCl  139-140                                                                             73.41 73.42                                                                      8.40 8.44                                                                        3.89 3.73                            3                                                                                 ##STR19##           HCl  170-171                                                                             71.80 72.06                                                                      7.61 7.72                                                                        4.41 4.44                            4                                                                                 ##STR20##           2HCl 187-191                                                                             63.57 63.65                                                                      7.56 7.32                                                                        6.18 6.35                            5                                                                                 ##STR21##           HCl  130-132                                                                             74.27 74.31                                                                      8.13 8.08                                                                        3.77 3.90                            6                                                                                 ##STR22##           2HCl 215-217                                                                             65.24 65.38                                                                      7.62 7.58                                                                        6.62 6.73                            7                                                                                 ##STR23##           HCl  135-136                                                                             73.83 73.71                                                                      7.88 7.92                                                                        3.91 3.79                            8                                                                                 ##STR24##           HCl  146-147                                                                             71.21 71.35                                                                      7.79 7.95                                                                        3.61 3.53                            9                                                                                 ##STR25##           HCl  152-155                                                                             71.21 71.22                                                                      7.79 7.86                                                                        3.61 3.87                            10                                                                                ##STR26##           2HCl 213-214                                                                             66.96 66.83                                                                      7.42 7.36                                                                        6.25 6.21                            11                                                                                ##STR27##           HCl  141-143                                                                             74.68  74.73                                                                     8.36 8.51                                                                        3.63 3.92                            __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________     ##STR28##               ED.sub.50Anti-MES                                                                    ED.sub.50Anti-PTZ                                                                     (mg/kg PO)LD.sub.50                   No.                                                                                 R                 (mg/kg PO)                                                                           (mg/kg PO)                                                                           Mice                                                                             Rat                                  __________________________________________________________________________        ##STR29##           38.0   17.8   1,300                                                                            2,000                                2  NHCH.sub.3           60.0   22.5   839                                                                              --                                   3                                                                                 ##STR30##           35.5   21.1   1,050                                                                            2,300                                4                                                                                 ##STR31##           76.1   16.3   1,050                                                                            --                                   5                                                                                 ##STR32##           60.0   <50* (100%)                                                                          621                                                                              --                                   6                                                                                 ##STR33##           20.0   14.0   415                                                                              --                                   7                                                                                 ##STR34##           65.0   <50*  (87.5%)                                                                        600                                                                              --                                   8                                                                                 ##STR35##           50* (40%)                                                                            <50* (85%)                                                                              --                                   9  Methotoin            91.3   51.9   475                                                                                2,500.sup.(a)                      10 Trimethadione        1,180  230    2,200                                                                            --                                   __________________________________________________________________________     *Inhibition %                                                                 .sup.(a) described in a book named "Iyakuhin Kenkyuho" (page 258)             published by "Asakura Shoten" (1968)                                     

As is apparent from Table 2, the antiepileptic efficacy of the compoundsNos. 1, 3 and 6 in Table 2 is much greater than that of trimethadioneand methotoin.

It is to be noted that the compounds Nos. 1 and 3 are preferred due totheir low level of toxicity.

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit of the invention as setforth herein.

What is claimed as new and intended to be covered by Letters Patentis:
 1. A compound having the formula (I): ##STR36## wherein R is --NR₁R₂ wherein R₁ and R₂, which may be the same or different, are eachselected from the group consisting of hydrogen and C₁ -C₅ alkyl or anacid addition salt thereof.
 2. The compound of claim 1, wherein R is--NR₁ R₂ wherein R₁ and R₂ are each selected from the group consistingof hydrogen and C₁ -C₃ alkyl.
 3. The compound of claim 2, wherein R is aC₁ -C₃ alkylamino or C₂ -C₆ dialkylamino group, which is unsubstitutedor substituted with a C₁ -C₄ alkyl, hydroxy or C₁ -C₃ hydroxyalkylgroup.
 4. The compound of claim 3 which is 2-(4-dimethylaminobutoxy)stilbene.
 5. A method of treating convulsions and seizures or relievingskeletal muscle spasm in warm-blooded animals which comprisesadministering to said animals an effective amount for treatment ofconvulsions and seizures or relief of skeletal muscle spasm of acompound of claim 1 or the acid addition salt thereof.
 6. Ananticonvulsant composition which comprises an anticonvulsant effectiveamount of a compound of claim 1 and a pharmaceutically acceptablecarrier.